Development and Validation of Innate Immunome-Targeted Therapy to Create Prosurvival and Organ-Protective Phenotype After Hemorrhage at the Point of Injury
Abstract
Severe bleeding (hemorrhage) post-trauma is the primary cause of death on the battlefield. Recent studies showed that 50% died of hemorrhage. In addition, bleeding is associated with 85% of potentially survivable deaths in the current conflicts. Approximately 90% of battlefield causalities die in the prehospital environment. The rate of death prior to evacuation increases from 20% with a 2-hour evacuation, to 26% with a 6-hour evacuation, and to 32% with a 24-hour evacuation. Of the increased deaths due to delayed evacuation, 62% are the result of hemorrhage. After arrival at a surgical facility and control of hemorrhage, casualties now enter a phase of care during which, according to a recent UK review, two-thirds of those who die do so because of causes other than exsanguination—to include unbridled inflammation and multi-organ failure (MOF). Mortality due to MOF after traumatic hemorrhage (TH) increases dramatically from 5% with single organ failure to 90% or more when at least four organ systems fail. The importance of better prehospital resuscitation strategies is highlighted by the fact that future combat casualty care scenarios suggest longer transport times and significant time delays in evacuation of casualties. Trauma-induced tissue damage, hemorrhage-induced ischemia injury, and fluid infusion-induced reperfusion injury cause activation of two major immune cascades: damage associated molecular patterns (DAMPs) and complement cascade (ComC), which trigger early immune response and metabolic derangement, thus resulting in systemic inflammatory response syndrome (SIRS), endotheliopathy (ETP), and persistent inflammation/immunosuppression and catabolism syndrome (PICS), which contribute to early MOF and mortality. Secondary organ/tissue damage and PICS-induced sepsis after TH lead to further release of DAMPs and ComC, resulting in a vicious cycle with continued inflammation and immune activation. However, no current immunotherapy exists that directly addresses TH-induced MOF and mortality at prolonged field care (PFC) and prolonged damage control resuscitation (PDCR) scenarios, a serious unmet need. Accumulating evidence suggests that early modulation of these two cascades may constitute the most effective therapeutic principle for the treatment of MOF and the improvement of survival after TH. Indeed, we have recently demonstrated that early inhibition of complement C5 by nomacopan or the inhibition of DAMPs by CX-01 significantly reduces inflammation, mitigates MOF, stabilize homeostasis, and improves survival in a rat model of TH at PFC and PDCR settings, suggesting that effective and timely resuscitation with nomacopan and/or CX-01 can attenuate morbidity and mortality after TH during PFC and PDCR. Recent reports indicated that PMX205 and ethyl pyruvate also repurposed drugs would act well in the combination with nomacopan and/or CX-01. These four immune modulators are manufactured under Good Manufacturing Practices. They are clinical-stage drugs and currently investigated in phase 2-3 for non-trauma indications that will place us in a position to move toward the appropriate U.S. Food and Drug Administration (FDA) Investigational New Drug (IND) application for phase 2 studies if this project proves to be successful. Furthermore, they are practical for transport and use on the battlefield; they can be carried in small vials, quickly reconstituted in small volumes of fluid, and administer by a single daily IM injection facilitating use in prehospital settings. Therefore, nomacopan, PMX205, CX-01, and ethyl pyruvate as a combinatorial therapeutic regimen in the prehospital setting may (1) reduce the weight and cube of resuscitation fluids and (2) reduce morbidity and mortality during PFC and PDCR. The proposed preclinical studies should be completed within 4 years of the funding period. Comprehensively, the successful outcome of this project will not only make a significant impact on new knowledge and inform
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310382
Entities
People
- Yansong Li
Organizations
- Geneva Foundation
- United States Army